Enantioselective synthesis of the tetrahydrofuran lignans (-)- and (+)-magnolone

Article abstract of DOI:10.1021/np070300v

The optically pure trisubstituted 7′-oxotetrahydrofuran lignans (-)- and (+)-magnolone (1) were synthesized by employing stereoselective S _N1 intramolecular cyclization as a key reaction. The absolute configuration of naturally occurring (-)-ma

Full text of DOI:10.1021/np070300v

1588
J. Nat. Prod. 2007, 70, 1588–1592
Enantioselective Synthesis of the Tetrahydrofuran Lignans (–)- and (+)-Magnolone
Tomofumi Nakato and Satoshi Yamauchi*
Faculty of Agriculture, Ehime UniVersity, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
ReceiVed June 22, 2007
The optically pure trisubstituted 7′-oxotetrahydrofuran lignans (-)- and (+)-magnolone (1) were synthesized by employing
stereoselective SN1 intramolecular cyclization as a key reaction. The absolute configuration of naturally occurring (-)-
magnolone was determined as (7S,8R,8′S).
(-)-Magnolone (1), a trisubstituted 7′-oxotetrahydrofuran lignan,
has been isolated from the leaves of Magnolia coco,1 and its relative
configuration has been proposed (Figure 1). M. coco has been used
as an herbal remedy for the treatment of impaired liver function
and cancer. There are only a few reports on the isolation of this
type of lignan.2 Trisubstituted tetrahydrofurans have interesting
structures, and some researchers have developed a synthesis route
to (-)-sesaminone.3,4 It is important to synthesize an optically pure
natural product and compare the specific rotation with that of the
natural product. The biosynthesis of lignans is complicated, and
some naturally occurring lignans are not optically pure.5,6 Naturally
occurring lignans may possess the same relative configuration, but
their absolute configuration may vary depending on their plant
source.7 Tetrahydrofuran lignans are pharmacologically important
compounds, so it is necessary to estimate the optical purity of the
isolated compound before using it in biological research. Here we
describe the synthesis of optically pure (-)- and (+)-magnolone
and comparison of the specific rotation of these compounds with
that of the natural compound. This is a new synthetic route to the
production of trisubstituted 7′-oxotetrahydrofuran lignans.
The key reaction in our synthesis is the stereoselective SN1
intramolecular etherification of the intermediates 2 and 3 to 4 in
the presence of acid as a catalyst. There is the possibility of the
competitive production of hemiacetals 5 and 6 under these reaction
conditions. Since oxygen atom attack on the benzylic carbocation
(Reaction Sequence 1) would be favored, the protective groups on
the primary and benzylic hydroxy groups (R1, R2, R3) are important
in avoiding production of hemiacetals (Reaction Sequences 2 and
3) (Scheme 1). Different protective groups for the primary hydroxy
groups (R1 and R2) require selective deprotection, thus increasing
the number of steps. It would be better if the protective groups (R1
and R2) were identical and the SN1 cyclization of 2 and 3 giving 4
could be carried out without deprotection.
benzylic proton (erythro 10: 2.9 Hz, threo 11: 7.3 Hz).9 Because
of its stability against hydride, which is used for the reduction of
lactone, the MOM ether was selected as the protective group for
the benzylic hydroxy group. After conversion of the aldol products
10 and 11 to the MOM ethers 12 and 13, the resulting lactones
were subjected to LiAlH4 reduction followed by cleavage of the
trityl ether in a formic acid–ether system, producing the corre-
sponding triols 14 and 15, respectively. Selective protection of the
primary hydroxy groups as pivaloyl esters followed by pyridinium
chlorochromate oxidation gave the ketones 18 and 19, respectively.
Next, the reaction conditions required for stereoselective SN1
cyclization of 18 and 19 were examined. Treatment of the ketone
18 with 6 M aqueous HCl solution in THF at room temperature
gave the trisubstituted tetrahydrofuran 20 with the desired config-
uration (41%) and 21 with undesired configuration (15%). The
ketone 19 gave 20 (40%) and 21 (17%) under the same reaction
conditions. An NOE association was observed between 7-H and
8′-H of 20. Employing camphorsulfonic acid in CH2Cl2 gave the
same result. The use of p-toluenesulfonic acid in CH2Cl2 showed
a decrease in stereoselectivity. The stereoselectivity for 20 was
increased (99% de) at 0 °C in 6 M aqueous HCl–THF; however,
the yield was decreased (22%), recovering ketone 18 (59%). A
longer reaction time at 0 °C did not increase the yield. In this
reaction, the attack of the 9′-oxygen on the 7-benzylic carbocation
from the opposite side of the 8-substituent was favored. The
formation of hemiacetals, which could be assumed to be produced
as by-products (Figure 1), was not observed, and the ketone 18 or
19 was recovered. The selective cyclization was achieved without
deprotection of the primary hydroxy group.
The hydrolysis of the pivaloyl ester 20 by exposure to aqueous
NaOH solution gave (-)-magnolone (1) with a yield of 88%. (+)-
Magnolone was also synthesized by the same method. The
enantiomeric excess of synthesized (-)- and (+)-magnolone (1)
was determined to be >>99% ee by employing a chiral column.
The absolute configuration of natural (-)-magnolone was deter-
mined to be (7S,8R,8′S) by the comparison of the specific rotation
Results and Discussion
The synthesis of the key intermediates 18 and 19 was started
from the syn-aldol product 78 (Scheme 2). The reductive removal
of the auxiliary of 7 and selective protection of the resulting primary
hydroxy group as trityl ether gave 8. After oxidative cleavage of
the olefin 8 by using the OsO4 oxidation–NaIO4 system, the
resulting unstable hemiacetal was converted to lactone 9 by
pyridinium chlorochromate oxidation. The aldol condensation of
lactone 9 with piperonal by using potassium hexamethyldisilazane
gave the erythro aldol product 10 (72%) and the threo aldol product
11 (21%). Since this new benzylic stereogenic center would be
converted to one stereogenic center through the production of a
benzylic carbocation, the erythro and threo selectivity at this stage
was unimportant. The configuration of the erythro and threo isomers
was determined from the coupling constant between 2-H and the
of the synthesized compounds ([R]20 -19) with reported data
D
([R]21 -11.25).1 This research demonstrates a new method for
D
synthesizing trisubstituted 7′-oxotetrahydrofuran lignans.
Experimental Section
General Experimental Procedures. Melting points were uncor-
rected. Optical rotations were measured on a Horiba SEPA-200
instrument. IR data were measured with a Horiba FT-720 instrument.
NMR data were obtained using a JNM-EX400 spectrometer. EI- and
FABMS data were measured with a JMS-MS700V spectrometer. The
silica gel used was Wakogel C-300 (Wako, 200–300 mesh). HPLC
analysis was performed with Shimadzu LC-6AD and SPD-6AV
instruments. The numbering of compounds follows IUPAC nomencla-
tural rules.
(3S,4R)-4-(3,4-Dimethoxyphenyl)-3-trityloxymethyl-4-butanolide (9).
To a solution of syn-aldol product 78 (14.0 g, 32.9 mmol) and MeOH
(3.07 mL, 75.8 mmol) in THF (200 mL) was added LiBH4 (1.65 g,
* To whom correspondence should be addressed. Tel: +81 89 946 9846.
Fax: +81-89-977-4364. E-mail: syamauch@agr.ehime-u.ac.jp.
10.1021/np070300v CCC: $37.00
2007 American Chemical Society and American Society of Pharmacognosy
Published on Web 09/22/2007

EnantioselectiVe Synthesis of (–)- and (+)-Magnolone
Journal of Natural Products, 2007, Vol. 70, No. 10 1589
Figure 1. (-)- and (+)-Magnolone (1).
Scheme 1. Desired SN1 Cyclization and Assumed Production of Hemiacetals as Artifacts
75.8 mmol) in THF (20 mL) at 0 °C, and then the resulting reaction
solution was stirred at 0 °C for 1 h before addition of 1 M aqueous
NaOH solution (100 mL) at 0 °C. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration of the organic
solvent gave a crude diol. A solution of the crude diol, trityl chloride
(10.3 g, 36.9 mmol), and 4-DMAP (70 mg, 0.57 mmol) in pyridine
(40 mL) was stirred at room temperature for 1 h before addition of
H2O and EtOAc. The organic solution was separated, washed with
saturated aqueous CuSO4 solution, saturatedurated aqueous NaHCO3
solution, and brine, and dried (Na2SO4). After evaporation of the organic
solution, the residue was applied to silica gel column chromatography
(EtOAc/n-hexane, 1:5 and 1:2) to give trityloxy olefin 8 (12.1 g, 24.5
trityloxy olefin 8 (12.1 g, 24.5 mmol), 4-methylmorpholine N-oxide
(4.0 g, 34.1 mmol), and OsO4 (aqueous 2% solution, 2.5 mL) in acetone
(230 mL), tert-BuOH (60 mL), and H2O (60 mL) was stirred at room
temperature for 12 h before addition of saturated aqueous Na2S2O3
solution. After the mixture was concentrated, the residue was dissolved
in EtOAc and H2O. The organic solution was separated, washed with
brine, and dried (Na2SO4). Evaporation of the solvent gave a crude
glycol. A mixture of the crude glycol and NaIO4 (6.89 g, 32.2 mmol)
in MeOH (100 mL) was stirred at room temperature for 1.5 h before
concentration of the reaction mixture. EtOAc (200 mL) and H2O (200
mL) were added to the residue. The organic solution was separated,
washed with brine, and dried (Na2SO4). Evaporation of the solvent and
subsequent Si column chromatography (EtOAc/n-hexane, 1:3) gave an
unstable hemiacetal (11.0 g, 22.2 mmol, 91%) as a colorless oil. A
mixture of the hemiacetal (11.0 g, 22.3 mmol) and PCC (6.82 g, 31.6
mmol) in CH2Cl2 (70 mL) containing MS 4 Å (0.6 g) was stirred at
room temperature for 13 h before addition of ether. After filtration,
the filtrate was concentrated. The residue was applied to Si column
chromatography (EtOAc/n-hexane, 1:3) to give lactone 9 (7.50 g, 15.2
mmol, 68%) as colorless crystals, which were recrystallized from
mmol, 74%, 2 steps) as a colorless oil: [R]20 -1 (c 0.2, CHCl3); IR
D
3500, 3010, 1259, 1139, 1029 cm-1; 1H NMR (CDCl3) δ 1.98 (1H, m,
C HCH(OH)Ar), 2.14–2.26 (2H, m, CH2dCHC H2CH), 3.12 (1H, d,
J ) 3.2 Hz, OH), 3.20 (1H, dd, J ) 9.4, 4.1 Hz, CHHOTr), 3.26 (1H,
dd, J ) 9.4, 4.1 Hz, CHHOTr), 3.81 (3H, s, OCH3), 3.84 (3H, s, OCH3),
4.86–4.95 (3H, m, ArC HOH, CH2dCH), 5.58 (1H, m, CHdCH2),
6.73–6.77 (2H, m, ArH), 6.85 (1H, s, ArH), 7.20–7.30 (9H, m, ArH),
7.40–7.42 (6H, m, ArH); 13C NMR (CDCl3) δ 30.3, 45.8, 55.76, 55.82,
64.1, 75.4, 87.2, 109.4, 110.8, 116.2, 118.4, 127.0, 127.8, 128.6, 135.2,
136.9, 143.7, 147.9, 148.6; FABMS m/z 495 ((M + 1)+, 1), 243 (100);
anal. C 80.33%, H 6.95%, calcd for C33H34O4, C 80.13%, H 6.93%.
EtOAc, mp 146–148 °C: [R]20 -4 (c 0.3, CHCl3); IR 1774, 1230,
D
1144, 1028 cm-1; H NMR (CDCl3) δ 2.62–2.73 (3H, m, 2-H, 3-H),
1
3.26 (1H, dd, J ) 9.7, 3.9 Hz, CHHOTr), 3.29 (1H, dd, J ) 9.7, 4.7
Hz, CHHOTr), 3.81 (3H, s, OCH3), 3.86 (3H, s, OCH3), 5.31 (1H, d,
(+)-Trityloxy olefin 8: [R]20 +1 (c 0.3, CHCl3). A solution of (-)-
D

1590 Journal of Natural Products, 2007, Vol. 70, No. 10
Scheme 2. Synthesis of (-)-Magnolone (1)a
Nakato and Yamauchi
a (a) (1) LiBH4, MeOH, THF, below 0 °C, 1 h; (2) TrCl, 4-DMAP, pyridine, rt, 1 h (74% yield, 2 steps); (b) (1) OsO4, NMO, aq acetone, tert-BuOH, rt, 12 h; (2)
NaIO4, MeOH, rt, 1.5 h; (3) PCC, MS 4A, CH2Cl2, rt, 13 h (68% yield, 3 steps); (c) KHMDS, piperonal, THF, -70 °C, 1 h (erythro 10: 74% yield, threo 11: 21%
yield); (d) (1) MOMCl, i-Pr2NEt, CH2Cl2, rt, 12 h (12: 95%, 13: 100% yield); (e) (1) LiAlH4, 0 °C, 30 min; (2) HCO2H, ether, 0 °C, 30 min (14: 54% yield, 2 steps,
15: 66% yield, 2 steps); (f) PivCl, pyridine, rt, 11 h (16: 80% yield, 17: 95% yield); (g) PCC, MS 4A, CH2Cl2, rt, 6 h (18: 68% yield, 19: 65% yield); (h) 6 M aq HCl
solution, THF, rt, 18 h (from 18: 20 (41% yield), 21 (15% yield), from 19: 20 (40% yield), 21 (17% yield); (i) 1 M aq NaOH solution, THF, rt, 12 h (88% yield).
J ) 6.2 Hz, 4-H), 6.71 (1H, dd, J ) 8.2, 1.9 Hz, ArH), 6.77 (1H, d, J
) 1.9 Hz, ArH), 6.79 (1H, d, J ) 8.2 Hz, ArH), 7.22–7.31 (9H, m,
ArH), 7.37–7.40 (6H, m, ArH); 13C NMR (CDCl3) δ 31.8, 44.6, 55.9,
62.0, 83.6, 86.8, 108.8, 110.9, 118.4, 127.2, 127.9, 128.5, 131.0, 143.4,
149.15, 149.18, 176.0; FABMS m/z 495 ((M + H)+, 3), 243 (50), 154
(100), 136 (65); anal. C 77.50%, H 6.12%, calcd for C32H30O5, C
127.1, 127.8, 128.5, 130.8, 133.9, 143.2, 147.4, 147.8, 149.1, 177.5;
FABMS m/z 645 ((M + H)+, 1), 154 (100), 136 (54); anal. C 74.85%,
H 5.76%, calcd for C40H36O8, C 74.51%, H 5.63%. (+)-11: [R]20D +44
(c 0.5, CHCl3).
(2S,3R)-2-(3,4-Dimethoxybenzoyl)-3-[(S)-(methoxymethoxy)(3,4-
methylenedioxy phenyl)methyl]tetramethylene dipivaloate (18). To
a solution of aldol product 10 (1.42 g, 2.20 mmol) and diisopropyl-
ethylamine (28.2 mL, 0.16 mol) in CH2Cl2 (5 mL) was added
chloromethyl methyl ether (6.15 mL, 0.081 mmol). After the reaction
solution was stirred at room temperature for 12 h, MeOH (6.6 mL),
CH2Cl2 (100 mL), and H2O (100 mL) were added. The organic solution
was separated, washed with brine, and dried (Na2SO4). After concentra-
tion of the solvent, the residue was applied to Si column chromatog-
raphy (EtOAc/n-hexane, 1:3) to give MOM ether 12 (1.44 g, 2.09 mmol,
77.71%, H 6.11%. (+)-9: [R]20 +4 (c 0.74, CHCl3).
D
(2S,3S,4R)-4-(3,4-Dimethoxyphenyl)-2-[(S)-hydroxy(3,4-methyl-
enedioxyphenyl)methyl]-3-trityloxymethyl-4-butanolide (10) and
(2S,3S,4R)-4-(3,4-dimethoxyphenyl)-2-[(R)-hydroxy(3,4-methylene-
dioxyphenyl)methyl]-3-trityloxymethyl-4-butanolide (11). To a
solution of KHMDS (8.70 mL, 0.5 M toluene solution, 4.35 mmol) in
THF (20 mL) was added a solution of lactone 9 (1.80 g, 3.64 mmol)
in THF (10 mL) at -70 °C. After stirring at -70 °C for 15 min, a
solution of piperonal (0.63 g, 4.20 mmol) in THF (5 mL) was added.
The resulting solution was stirred at -70 °C for 1 h before addition of
a saturated aqueous NH4Cl solution. The organic solution was separated,
washed with brine, and dried (Na2SO4). After evaporation of the solvent,
the residue was applied to Si column chromatography (EtOAc/toluene,
7:93) to give erythro product 10 (1.74 g, 2.70 mmol, 74%) as a colorless
oil and threo product 11 (0.51 g, 0.78 mmol, 21%) as a colorless oil.
95%) as a colorless oil: [R]20 -121 (c 1.1, CHCl3); IR 3026, 2958,
D
1766, 1241, 1182, 1095, 1027 cm-1; H NMR (CDCl3) δ 2.77 (1H,
1
dd, J ) 9.3, 4.9 Hz, CHHOTr), 2.89 (1H, d, J ) 9.3 Hz, CHHOTr),
2.96 (1H, m, 3-H), 3.25 (1H, d, J ) 8.9 Hz, 2-H), 3.41 (3H, s, OCH2OC
H3), 3.82 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.62 (1H, d, J ) 6.1 Hz,
OCHHOCH3), 4.64 (1H, d, J ) 6.1 Hz, OCHHOCH3), 5.05 (1H, d, J
) 7.8 Hz, 4-H), 5.38 (1H, s, ArCHOMOM), 5.90 (1H, s, OC HHO),
5.94 (1H, s, OCH HO), 6.52 (1H, d, J ) 8.1 Hz, ArH), 6.69–6.78 (4H,
m, ArH), 6.83 (1H, s, ArH), 7.21–7.25 (15H, m, ArH); 13C NMR
(CDCl3) δ 43.9, 49.5, 55.8, 55.9, 56.3, 60.7, 74.7, 82.4, 86.5, 94.8,
101.1, 106.3, 108.6, 109.4, 110.6, 119.4, 119.5, 127.0, 127.8, 128.5,
132.26, 132.28, 143.3, 147.2, 148.0, 149.1, 149.2, 176.2; EIMS m/z
(%) 688 (M+, 45), 383 (70), 244 (84), 243 (99), 195 (72), 165 (100);
HREIMS m/z 688.2675 (calcd for C42H40O7, 688.2661). (+)-MOM ether
12: [R] 20D +121 (c 0.67, CHCl3).To an ice-cooled suspension of LiAlH4
(0.36 g, 9.49 mmol) in THF (50 mL) was added a solution of MOM
ether 12 (1.10 g, 1.60 mmol) in THF (10 mL). The resulting mixture
was stirred at 0 °C for 30 min before addition of a saturated aqueous
MgSO4 solution and K2CO3. After stirring for 30 min, the mixture was
filtered. The filtrate was concentrated to give a crude diol. To a solution
of the crude diol in ether (45 mL) was added formic acid (57 mL) at
0 °C. After the solution was stirred at 0 °C for 30 min, CHCl3 (100
mL) and H2O (100 mL) were added. The organic solution was
separated, washed with a saturated aqueous NaHCO3 solution and brine,
and dried (Na2SO4). Concentration of the solvent followed by Si column
chromatography (EtOAc/n-hexane, 2:1) gave (-)-triol 14 (0.39 g, 0.87
Erythro 10: [R]20 -77 (c 0.2, CHCl3); IR 3608, 2886, 1760, 1240,
D
1
1184, 1041 cm-1; H NMR (CDCl3) δ 2.76 (1H, dd, J ) 9.2, 5.1 Hz,
CHHOTr), 2.84 (1H, m, 3-H), 2.89 (1H, dd, J ) 9.3, 3.6 Hz, CHHOTr),
3.22 (1H, s, OH), 3.26 (1H, dd, J ) 9.3, 2.9 Hz, 2-H), 3.76 (3H, s,
OCH3), 3.84 (3H, s, OCH3), 5.05 (1H, d, J ) 8.0 Hz, 4-H), 5.40 (1H,
d, J ) 2.9 Hz, ArCHOH), 5.88 (1H, s, OCHHO), 5.90 (1H, s, OCHHO),
6.52 (1H, dd, J ) 8.2, 1.9 Hz, ArH), 6.66 (1H, d, J ) 7.9 Hz, ArH),
6.70 (1H, d, J ) 8.2 Hz, ArH), 7.20–7.26 (15H, m, ArH); 13C NMR
(CDCl3) δ 43.7, 50.2, 55.79, 55.82, 60.9, 71.0, 82.9, 86.6, 101.0, 105.9,
108.3, 109.7, 110.5, 118.5, 119.7, 127.0, 127.8, 128.5, 131.7, 135.0,
143.3, 146.8, 147.8, 149.1, 149.3, 177.3; FABMS m/z 645 ((M + H)+,
1), 154 (100), 136 (65); anal. C 74.64%, H 5.74%, calcd for C40H36O8,
C 74.51%, H 5.63%. (+)-10: [R]20 +77 (c 0.3, CHCl3). Threo 11:
D
[R]20 -45 (c 0.2, CHCl3); IR 3608, 2886, 1760, 1240, 1164, 1044
D
cm-1; 1H NMR (CDCl3) δ 2.42 (1H, m, 3-H), 2.91–2.97 (2H, m,
CH2OTr), 3.16 (1H, dd, J ) 8.6, 7.3 Hz, 2-H), 3.73 (3H, s, OCH3),
3.85 (3H, s, OCH3), 4.03 (1H, d, J ) 2.4 Hz, OH), 4.95 (1H, dd, J )
7.3, 2.4 Hz, ArCHOH), 5.08 (1H, d, J ) 8.3 Hz, 4-H), 5.88 (2H, s,
OCH2O), 6.45 (1H, d, J ) 8.2 Hz, ArH), 6.51 (1H, s, ArH), 6.64 (1H,
d, J ) 7.9 Hz, ArH), 6.70–6.74 (2H, m, ArH), 6.84 (1H, s, ArH),
7.15–7.24 (15H, s, ArH); 13C NMR (CDCl3) δ 46.5, 49.7, 55.8, 55.9,
61.4, 74.0, 82.8, 87.0, 101.0, 107.0, 108.1, 109.1, 110.8, 119.1, 120.1,
mmol, 54%) as a colorless oil: [R]20 -38 (c 0.78, CHCl3); IR 3400,
D
1
2935, 1444, 1246, 1140, 1028 cm-1; H NMR (CDCl3) δ 1.90-2.10
(1Η, br, OH), 2.19 (1H, m, CH), 2.48 (1H, m, CH), 3.27 (1H, dd, J )

EnantioselectiVe Synthesis of (–)- and (+)-Magnolone
Journal of Natural Products, 2007, Vol. 70, No. 10 1591
8.8, 1.3 Hz, CHHOH), 3.35 (1H, dd, J ) 10.8, 5.3 Hz, CHHOH), 3.43
(3H, s, OCH2OCH3), 3.65 (1H, dd, J ) 10.8, 2.7 Hz, CHHOH), 3.73
(1H, dd, J ) 8.8, 7.6 Hz, CHHOH), 3.76–3.90 (1H, br, OH), 3.87
(3H, s, OCH3), 3.89 (3H, s, OCH3), 4.55 (2H, s, OC H2OCH3), 4.56
(1H, br s, OH), 4.84 (1H, d, J ) 9.5 Hz, ArCHOMOM), 4.90 (1H, br
d, J ) 6.3 Hz, ArCHOH), 5.94 (1H, d, J ) 3.4 Hz, OCHHO), 5.95
(1H, d, J ) 3.4 Hz, OCH HO), 6.73–6.78 (3H, m, ArH), 6.85 (1H, d,
J ) 7.7 Hz, ArH), 6.91–6.94 (2H, m, ArH); 13C NMR (CDCl3) δ 46.4,
49.5, 55.8, 55.9, 56.9, 63.0, 63.5, 73.5, 94.5, 101.1, 107.3, 108.1, 109.2,
111.0, 118.3, 121.4, 133.6, 136.6, 147.4, 147.9, 148.0, 148.9; FABMS
m/z 451 ((M + H)+, 1), 251 (78), 154 (100), 136 (73); anal. C 61.19%,
m, CH), 1.82 (1H, br s, OH), 2.33 (1H, m, CH), 3.26 (1H, dd, J )
11.6, 5.8 Hz, CHHOH), 3.31 (1H, dd, J ) 11.6, 3.7 Hz, CHHOH),
3.39 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.84 (3H, s, OCH3), 4.07
(1H, dd, J ) 11.4, 3.5 Hz, CHHOH), 4.15 (1H, dd, J ) 11.4, 5.9 Hz,
CHHOH), 4.50 (2H, s, OCH2OCH3), 4.74 (1H, d, J ) 9.5 Hz,
ArCHOMOM), 5.07 (1H, d, J ) 8.9 Hz, ArCHOH), 5.95 (2H, s,
OCH2O), 6.75–6.79 (4H, m, ArH), 6.88–6.91 (2H, m, ArH); 13C NMR
(CDCl3) δ 47.5, 48.2, 55.7, 55.9, 56.0, 60.7, 63.7, 73.6, 80.2, 94.6,
101.0, 107.8, 108.0, 109.3, 110.7, 119.0, 122.1, 134.5, 136.3, 147.2,
147.9, 148.5, 149.0; EIMS m/z (%) 450 (M+, 6), 432 (55), 370 (98),
195 (100); HREIMS m/z 450.1890 (calcd for C23H30O9, 450.1890).
Hydroxydipivaloate 17. 95% yield; colorless oil: [R]20 +73 (c 0.2,
H 6.73%, calcd for C23H30O9, C 61.31%, H 6.72%. (+)-triol 14: [R]20
D
D
1
CHCl3); IR 2971, 1718, 1243, 1157, 1029 cm-1; H NMR (CDCl3) δ
+38 (c 0.85, CHCl3). To an ice-cooled solution of the (-)-triol 14
(0.43 g, 0.95 mmol) in pyridine (7 mL) was added PivCl (0.30 mL,
2.44 mmol). The resulting mixture was stirred at room temperature for
11 h. After addition of EtOAc (100 mL) and H2O (100 mL), the organic
solution was separated, washed with 1 M aqueous HCl solution,
saturated aqueous NaHCO3 solution, and brine, and dried (Na2SO4).
After evaporation of the solvent, the residue was applied to Si column
chromatography (EtOAc/n-hexane, 1:3) to give (-)-hydroxydipivaloate
1.11 (9H, s, tert-Bu), 1.20 (9H, s, tert-Bu), 2.08 (1H, m, CH), 2.43
(1H, d, J ) 2.3 Hz, OH), 2.55 (1H, m, CH), 3.39 (3H, s, OCH2OCH3),
2.64 (1H, dd, J ) 11.2, 5.4 Hz, CHHOPiv), 3.83 (3H, s, OCH3), 3.84
(3H, s, OCH3), 3.99 (1H, dd, J ) 11.2, 8.3 Hz, OCHHOPiv), 4.49
(1H, d, J ) 6.8 Hz, OCHHOCH3), 4.53 (1H, d, J ) 6.8 Hz, OCH
HOCH3), 4.51–4.61 (3H, m, OCH2OPiv, ArCHOH), 5.09 (1H, d, J )
8.2 Hz, ArCHOMOM), 5.95 (1H, d, J ) 7.8 Hz, OCHHO), 5.96 (1H,
d, J ) 7.8 Hz, OCH HO), 6.70 (1H, dd, J ) 8.1, 1.8 Hz, ArH), 6.73
(1H, d, J ) 1.8 Hz, ArH), 6.77 (1H, d, J ) 8.1 Hz, ArH), 6.80 (1H,
d, J ) 8.3 Hz, ArH), 6.92–6.94 (2H, m, ArH); 13C NMR (CDCl3) δ
27.1, 27.2, 38.6, 38.7, 43.7, 44.3, 55.6, 55.9, 56.3, 63.3, 64.5, 73.8,
78.5, 94.5, 101.0, 107.8, 108.1, 109.0, 110.9, 119.0, 122.0, 134.5, 135.6,
147.2, 147.8, 148.8, 149.3, 178.2, 178.4; FABMS m/z 619 ((M + H)+,
0.5), 165 (100); anal. C 63.93%, H 7.60%, calcd for C33H46O11, C
64.05%, H 7.50%. Ketone 19. 65% yield; colorless oil: [R]20D +35 (c
16 (0.47 g, 0.76 mmol, 80%) as a colorless oil: [R]20 -45 (c 0.9,
D
1
CHCl3); IR 2445, 2972, 1724, 1155, 1026 cm-1; H NMR (CDCl3) δ
1.16 (9H, s, tert-Bu), 1.18 (9H, s, tert-Bu), 2.44 (1H, m, CH), 2.57
(1H, m, CH), 3.48 (3H, s, OCH2OCH3), 3.87 (3H, s, OCH3), 3.91 (3H,
s, OCH3), 3.94–4.06 (5H, m, CH2OPiv, OH), 4.60 (2H, s, OCH2OCH3),
4.76 (1H, dd, J ) 7.3, 4.8 Hz, ArCHOH), 4.83 (1H, d, J ) 7.9 Hz,
ArCHOMOM), 5.96 (2H, s, OCH2O), 6.72–6.78 (3H, m, ArH),
6.83–6.86 (2H, m, ArH), 6.93 (1H, s, ArH); 13C NMR (CDCl3) δ 27.1,
38.7, 43.1, 44.4, 55.8, 55.9, 57.0, 64.5, 64.6, 72.3, 94.3, 101.2, 107.1,
108.2, 109.3, 111.1, 118.6, 121.1, 132.8, 136.0, 147.6, 148.2, 148.4,
149.1, 178.0, 178.1; FABMS m/z 619 ((M + H)+, 1), 453 (62), 165
(100); anal. C 63.42%, H 7.61%, calcd for C33H46O11, C 64.05%, H
1
0.9, CHCl3); IR 2971, 1722, 1670, 1263, 1155, 1025 cm-1; H NMR
(CDCl3) δ 1.03 (9H, s, tert-Bu), 1.13 (9H, s, tert-Bu), 2.55 (1H, m,
2-H), 3.40 (3H, s, OCH2OCH3), 3.91 (3H, s, OCH3), 3.94 (3H, s,
OCH3), 4.03 (1H, m, 3-H), 4.26 (1H, dd, J ) 11.8, 4.9 Hz, CHHOPiv),
4.41 (1H, dd, J ) 11.8, 6.3 Hz, CHHOPiv), 4.48–4.52 (4H, m,
CH2OPiv, OCH2OCH3), 4.73 (1H, d, J ) 5.4 Hz, ArCHOMOM), 5.93
(2H, s, OCH2O), 6.62 (1H, dd, J ) 8.4, 1.6 Hz, ArH), 6.69–6.71 (2H,
m, ArH), 6.83 (1H, d, J ) 8.4 Hz, ArH), 7.43 (1H, d, J ) 2.0 Hz,
ArH), 7.47 (1H, dd, J ) 8.4, 2.0 Hz, ArH); 13C NMR (CDCl3) δ 27.0,
27.1, 38.60, 38.64, 43.4, 45.0, 55.9, 56.1, 56.4, 62.4, 64.1, 76.6, 94.6,
101.1, 107.3, 108.1, 109.8, 110.5, 121.0, 123.0, 130.5, 132.9, 147.3,
147.9, 149.1, 153.5, 178.1, 198.8; EIMS m/z (%) 616 (M+, 0.1), 192
(100), 165 (78); HREIMS m/z 616.2883 (calcd for C33H44O11, 616.2884).
(2S,3R,4S)-4-(3,4-Dimethoxybenzoyl)-2-(3,4-methylenedioxyphenyl)-
3-(pivaloyloxymethyl)tetrahydrofuran [(7S,8R,8′S)-3′,4′-dimethoxy-3,4-
methylenedioxy-7′-oxo-7,9′-epoxylignan-9-ylpivaloate](20)and(2R,3R,4S)-
4-(3,4-Dimethoxybenzoyl)-2-(3,4-methylenedioxyphenyl)-3-
(pivaloyloxymethyl)tetrahydrofuran [(7R,8R,8′S)-3′,4′-dimethoxy-3,4-
methylenedioxy-7′-oxo-7,9′-epoxylignan-9-yl pivaloate] (21). A solution
of ketone 18 (68.0 mg, 0.11 mmol) in THF (3 mL) and 6 M aqueous
HCl solution (3 mL) was stirred at room temperature for 18 h before
addition of H2O (50 mL) and EtOAc (50 mL). The organic phase was
separated, washed with brine, and dried (Na2SO4). After evaporation of
the organic solvent, the residue was applied to Si column chromatography
(EtOAc/hexane, 1:5) to give tetrahydrofuran 20 (21 mg, 0.045 mmol, 41%)
as a colorless oil and tetrahydrofuran 21 (8 mg, 0.017 mmol, 15%) as a
colorless oil. Tetrahydrofuran 20 (40% yield) and tetrahydrofuran 21 (17%
yield) were obtained from ketone 19. Tetrahydrofuran 20: [R]20D -8 (c
0.52, CHCl3); IR 2962, 1724, 1671, 1265, 1162, 1041 cm-1; 1H NMR
(CDCl3) δ 1.11 (9H, s, tert-Bu), 3.08 (1H, m, 3-H), 3.95 (3H, s, OCH3),
3.96 (3H, s, OCH3), 4.06 (1H, m, 4-H), 4.13–4.17 (3H, m, 5-H2,
CHHOPiv), 4.27 (1H, dd, J ) 8.7, 8.7 Hz, CHHOPiv), 4.62 (1H, d, J
) 9.0 Hz, 2-H), 5.96 (2H, s, OCH2O), 6.78 (1H, d, J ) 8.0 Hz, ArH),
6.86 (1H, d, J ) 8.0 Hz, ArH), 6.91 (1H, d, J ) 8.4 Hz, ArH), 6.99
(1H, s, ArH), 7.56 (1H, s, ArH), 7.53 (1H, d, J ) 8.4 Hz, ArH); 13C
NMR (CDCl3) δ 27.1, 38.8, 49.6, 49.8, 56.0, 56.1, 62.9, 71.1, 84.2,
101.1, 107.2, 108.1, 110.1, 110.6, 120.5, 122.9, 129.7, 133.8, 147.6,
148.0, 149.4, 153.8, 178.2, 196.6; EIMS m/z (%) 470 (M+, 35), 203
(86), 165 (100); HREIMS m/z 470.1940 (calcd for C26H30O8, 470.1940).
(+)-20: [R]20D +8 (c 0.65, CHCl3). Tetrahydrofuran 21: [R]20D +88 (c
7.50%. (+)-Hydroxy dipivaloate 16: [R]20 +45 (c 1.6, CHCl3). A
D
mixture of (-)-hydroxydipivaloate (0.47 g, 0.76 mmol), PCC (0.23 g,
1.07 mmol), and MS 4 Å (20 mg) in CH2Cl2 (10 mL) was stirred at
room temperature for 6 h before addition of ether. After the mixture
was filtered, the filtrate was concentrated. The residue was applied to
Si column chromatography (EtOAc/n-hexane, 1:6) to give (-)-ketone
18 (0.32 g, 0.52 mmol, 68%) as a colorless oil: [R]20 -77 (c 0.62,
D
CHCl3); IR 2974, 1724, 1670, 1481, 1246, 1155, 1026 cm-1; 1H NMR
(CDCl3) δ 1.02 (9H, s, tert-Bu), 1.12 (9H, s, tert-Bu), 2.44 (1H, m,
3-H), 3.27 (3H, s, OCH2OCH3), 3.94 (3H, s, OCH3), 3.96 (3H, s,
OCH3), 4.11 (1H, dd, J ) 11.9, 6.2 Hz, CHHOPiv), 4.22 (1H, m, 2-H),
4.28 (1H, dd, J ) 11.9, 4.6 Hz, CHHOPiv), 4.33 (1H, d, J ) 6.5 Hz,
OCHHOCH3), 4.40 (1H, d, J ) 6.5 Hz, OCHHOCH3), 4.37 (1H, dd,
J ) 10.7, 6.4 Hz, CHHOPiv), 4.49 (1H, dd, J ) 10.7, 8.4 Hz, CH
HOPiv), 4.66 (1H, d, J ) 6.4 Hz, ArCHOMOM), 5.95 (2H, s, OCH2O),
6.66 (1H, d, J ) 7.9 Hz, ArH), 6.69 (1H, s, ArH), 6.74 (1H, d, J ) 7.9
Hz, ArH), 6.90 (1H, d, J ) 8.5 Hz, ArH), 7.53 (1H, d, J ) 1.7 Hz,
ArH), 7.64 (1H, dd, J ) 8.5, 1.7 Hz, ArH); 13C NMR (CDCl3) δ 27.0,
27.1, 38.6, 42.6, 46.1, 56.0, 56.1, 56.3, 62.9, 64.9, 94.5, 101.1, 107.0,
108.1, 109.8, 110.5, 120.7, 123.0, 131.1, 133.5, 147.3, 148.0, 149.0,
153.3, 177.9, 178.1, 199.1; EIMS m/z (%) 616 (M+, 0.5), 192 (100);
anal. C 63.99%, H 7.09%, calcd for C33H44O11, C 64.26%, H 7.20%.
(+)-Ketone 18: [R]20 +77 (c 0.93, CHCl3).
D
(2S,3R)-2-(3,4-Dimethoxybenzoyl)-3-[(R)-(methoxymethoxy)(3,4-
methylenedioxyphenyl)methyl]tetramethylene dipivaloate (19).
MOM ether 13. 100% yield; colorless oil: [R]20D +58 (c 0.2, CHCl3);
1
IR 3025, 2958, 1766, 1489, 1442, 1242, 1162, 1029 cm-1; H NMR
(CDCl3) δ 2.47 (1H, m, 3-H), 3.19 (1H, dd, J ) 9.5, 2.9 Hz, CHHOTr),
3.35 (3H, s, OCH2OCH3), 3.46 (1H, dd, J ) 9.5, 4.9 Hz, CHHOTr),
3.59 (1H, dd, J ) 9.9, 3.5 Hz, 2-H), 3.64 (3H, s, OCH3), 3.83 (3H, s,
OCH3), 4.54 (1H, d, J ) 6.4 Hz, OCHHOCH3), 4.56 (1H, d, J ) 6.4
Hz, OCHHOCH3), 5.14 (1H, d, J ) 8.4 Hz, ArCHOMOM), 5.34 (1H,
d, J ) 3.5 Hz, 4-H), 5.90 (1H, s, OCHHO), 5.91 (1H, s, OCHHO),
6.23–6.25 (2H, m, ArH), 6.61 (1H, d, J ) 8.7 Hz, ArH), 6.72–6.76
(2H, m, ArH), 6.78 (1H, s, ArH), 7.24–7.33 (9H, m, ArH), 7.40–7.42
(6H, m, ArH); 13C NMR (CDCl3) δ 46.0, 48.8, 55.6, 55.8, 55.9, 60.3,
75.6, 81.9, 86.8, 94.2, 101.1, 107.8, 108.2, 108.5, 110.4, 119.2, 121.1,
127.1, 127.9, 128.7, 131.1, 131.3, 143.5, 147.3, 147.7, 149.07, 149.10,
175.2; EIMS m/z (%) 688 (M+, 15), 244 (70), 243 (80), 165 (100);
anal. C 73.52%, H 5.81%, calcd for C42H40O9, C 73.24%, H 5.85%.
Triol 15. 66% yield (2 steps); colorless oil: [R]20D +109 (c 0.89, CHCl3);
IR 3400, 3010, 2937, 1249, 1027 cm-1; 1H NMR (CDCl3) δ 1.78 (1H,
1
0.2, CHCl3); IR 2927, 1724, 1670, 1508, 1263, 1151, 1041 cm-1; H
NMR (CDCl3) δ 0.96 (9H, s, tert-Bu), 2.80 (1H, m, 3-H), 3.93 (3H, s,
OCH3), 3.95 (3H, s, OCH3), 4.04 (1H, dd, J ) 11.5, 6.7 Hz, CHHOPiv),
4.13 (1H, dd, J ) 11.5, 7.1 Hz, CHHOPiv), 4.25–4.33 (2H, m, 5-H2),
4.35 (1H, m, 4-H), 4.86 (1H, d, J ) 6.7 Hz, 2-H), 5.97 (2H, s, OCH2O),
6.79–6.90 (4H, m, ArH), 7.54–7.55 (2H, m, ArH); 13C NMR (CDCl3)

1592 Journal of Natural Products, 2007, Vol. 70, No. 10
Nakato and Yamauchi
δ 26.9, 38.5, 46.8, 50.7, 56.0, 56.1, 62.2, 70.5, 83.7, 101.1, 106.4, 108.3,
110.0, 110.2, 119.7, 122.9, 130.4, 135.1, 147.3, 148.0, 149.4, 153.8,
178.0, 197.1; EIMS m/z (%) 470 (M+, 16), 368 (95), 203 (98), 193
(98), 165 (100); HREIMS m/z 470.1941 (calcd for C26H30O8, 470.1941).
(2S,3R,4S)-4-(3,4-Dimethoxybenzoyl)-3-hydroxymethyl-2-(3,4-
methylenedioxyphenyl)tetrahydrofuran ((-)-magnolone, 1). To a
solution of (-)-pivaloate 20 (15 mg, 0.032 mmol) in EtOH (1 mL)
was added a 1 M aqueous NaOH solution (1 mL). The resulting solution
was stirred at room temperature for 12 h before addition of EtOAc (50
mL) and H2O (50 mL). The organic solution was separated, washed
with brine, and dried (Na2SO4). After concentration of the solvent, the
residue was applied to Si column chromatography (EtOAc/n-hexane,
1:1) to give (-)-magnolone [(-)-1] (11 mg, 0.028 mmol, 88%) as a
colorless oil: IR 3748, 3025, 1670, 1263, 1160, 1041 cm-1; NMR data
agreed with literature;1 [R]20 -31 (c 0.2, CHCl3), [R]20 -19 (c 0.4,
Acknowledgment. The 400 MHz NMR and IR data were measured
at INCS, Ehime University. We thank the staff at this center for the
MS measurement. We are also grateful to Marutomo Co., Iyo, Ehime,
Japan.
References and Notes
(1) Yu, H.-J.; Chen, C.-C.; Shieh, B.-J. J. Nat. Prod. 1998, 61, 1017–1019.
(2) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75–96.
(3) Maioli, A. T.; Civiello, R. L.; Foxman, B. M.; Gordon, D. M. J. Org.
Chem. 1997, 62, 7413–7417.
(4) Yoda, H.; Kimura, K.; Takabe, K. Synlett 2001, 3, 400–402.
(5) Suzuki, S.; Umezawa, T.; Shimada, M. Biosci. Biotechnol. Biochem.
2002, 66, 1262–1269.
(6) Umezawa, T.; Okunishi, T.; Shimada, M. Wood Res. 1997, 84, 62–75.
(7) Ayres, D. C.; Loike. J. D. Lignans; Cambridge University Press, 1990.
(8) Yamauchi, S.; Okazaki, M.; Akiyama, K.; Sugahara, T.; Kishida, T.;
Kashiwagi, T. Org. Biomol. Chem. 2005, 3, 1670–1675.
(9) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D. J. Am.
Chem. Soc. 1973, 95, 3310–3324.
D
D
MeOH), lit.:1 [R]21D -11.25 (c 0.4, MeOH); EIMS m/z (%) 386 (M+,
42), 165 (100); HREIMS m/z 386.1367 (calcd for C21H22O7, 386.1365);
more than 99% ee (HPLC, DAICEL chiral column OD-H, detected at
280 nm, 1 mL min-1, 10% EtOH in hexane, tR 48 min). (+)-Magnolone:
[R]20 +31 (c 0.2, CHCl3), > 99% ee (tR 43 min).
NP070300V
D